C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients

A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in ‘non-expansion’ patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5–17% of patients (21–41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine ‘expansion-positive’ patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an ‘intermediate’ allele with a mean size of only ~65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of ‘non-expansion’ FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ~65 repeats may be sufficient to cause disease.Carol Dobson-Stone, Marianne Hallupp, Clement T. Loy, Elizabeth M. Thompson, Eric Haan, Carolyn M. Sue, Peter K. Panegyres, Cristina Razquin, Manuel Seijo-Martínez, Ramon Rene, Jordi Gascon, Jaume Campdelacreu, Birgit Schmoll, Alexander E. Volk, William S. Brooks, Peter R. Schofield, Pau Pastor, John B. J. Kwo

C9ORF72 Repeat Expansion in Australian and Spanish Frontotemporal Dementia Patients

A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in 'non-expansion' patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5-17% of patients (21-41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine 'expansion-positive' patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an 'intermediate' allele with a mean size of only similar to 65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of 'non-expansion' FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as similar to 65 repeats may be sufficient to cause disease

Analysis of <i>C9ORF72</i> expansion allele size.

<p>A, Southern blot analysis of five unrelated probands and four Aus-14 family members with the <i>C9ORF72</i> repeat expansion, plus an expansion-negative control (N). Wild-type (wt) and expansion (exp) alleles are indicated; the smaller expansion allele in case 100 is arrowed. A band running at ∼3.8 kb was also observed (asterisk); this probably arises from unspecific probe binding. B, Scatter plot of age of onset of disease versus estimated mean number of <i>C9ORF72</i> hexanucleotide repeats in expansion allele carriers.</p

Disease characteristics of 17 <i>C9ORF72</i> mutation carriers.

<p>Data presented only for those <i>C9ORF72</i>-positive cases not previously reported. Details of six additional <i>C9ORF72</i>-positive cases have been reported previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056899#pone.0056899-DobsonStone1" target="_blank">[8]</a>.</p><p>AD = Alzheimer's disease, bvFTD = behavioural variant FTD, d41 = died at age 41, DLB = dementia with Lewy bodies, F = female, FH = family history, FTD-ALS = FTD with amyotrophic lateral sclerosis, M = male, PBP = pseudobulbar palsy, scz = schizophrenia; SMD = semantic dementia, N/A = data not available.</p>*<p>Data for family members is in parentheses.</p

Demographic information of FTD patient groups.

<p>bvFTD = behavioural variant FTD; CBS = corticobasal syndrome; D = death; F = female; FTD-ALS = FTD with amyotrophic lateral sclerosis; FTDP = FTD with parkinsonism; FTDm = FTD with mixed phenotype; FTDuns = FTD otherwise unspecified; M = male; PNFA = progressive non-fluent aphasia; SMD = semantic dementia.</p>*<p>Gender information not available for one patient.</p